Overt hypothyroid is defined as an elevated pituitary thyrotropin (TSH) and corresponding low thyroid hormone levels, while the much more common entity, subclinical hypothyroidism (SCH), is defined as an elevated TSH but normal thyroid hormone levels. SCH is particularly common among individuals over age 50 and may be associated with adverse cardiovascular and neuropsychiatric outcomes. Recent studies suggest that subclinical hypothyroidism is associated with a two-fold increase in clinical congestive heart failure and a 20-50% increased risk of ischemic heart disease. Small trials of thyroid hormone replacement have reported positive effects on surrogate cardiovascular outcomes, such as lipoproteins, cardiac function, and intima-media thickness. However, no large clinical trials have evaluated effective treatment to reduce the morbidity associated with subclinical hypothyroidism and improve clinical outcomes. Lacking conclusive evidence, wide variations in clinical practice have emerged, with some clinicians actively screening for and treating subclinical hypothyroidism, while others do neither. In 2004 the US Preventive Services Task Force noted the paucity of data regarding treatment of subclinical thyroid disorders and concluded that there was insufficient evidence to recommend for or against screening for thyroid dysfunction. This proposal will support planning activities for a large double-blind, multi-center trial of men and women 50-85 years old with persistent subclinical hypothyroidism recruited by population-based screening and randomized to either thyroxine replacement to normalize TSH, or matching placebo. The primary endpoints will be clinical cardiovascular outcomes, specifically heart failure, ischemic heart disease, or cardiovascular death, with secondary neuropsychiatric, musculoskeletal, and functional outcomes. The planning process for this trial will include a broad coalition of investigators with expertise in thyroid dysfunction, cardiovascular and neuropsychiatric outcomes, and clinical trial methodology. The product of this planning process will be a full-scale clinical trial application to the NIH, including a detailed protocol and organization structure, complete manual of operations, feasibility data regarding population-screening for abnormal thyroid function and a comprehensive description of the proposed activities of the investigators, clinical centers, and San Francisco Coordinating Center. PUBLIC HEALTH RELEVANCE: Subclinical hypothyroidism, sometimes called mild thyroid failure, is particularly common in older individuals and may be associated with adverse cardiovascular, neuropsychiatric, and neuromuscular outcomes. In this multi-center planning grant we request support to design a large randomized, placebo-controlled trial to determine if, compared to placebo, treatment of subclinical hypothyroidism with thyroid hormone replacement is associated with improved cardiovascular and neuropsychiatric outcomes. This trial will provide high quality evidence on the utility of screening for and treating subclinical hypothyroidism in older individuals.